Throughout this application, various publications are referenced and full citations for these publications may be found in the references at the end of the specifications preceding the claims. The disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to the skilled therein as of the date of the invention described and claimed herein.
Menstrual cramps and dysfunctional uterine bleeding are common disorders among women during their menstrual period. Menstrual cramps affect as many as 40 percent of female adults and temporarily disables one-tenth of them. As a newly developed treatment, the present inventionxe2x80x94Cinnamomi and Poria composition, which originated from an old Chinese herb formula, is effective in relieving symptoms of such diseases or disorders.
Menstrual cramps, or dysmenorrhea, as it is called in medical terms, is the reoccurrence of painful uterine cramps during menstruation. Dysmenorrhea can include crampy pain; discomfort in the lower abdomen, lower back and the inner thighs; nausea; vomiting; headache; diarrhea; or fatigue. It normally has an onset of from 2-12 hours before the start of menses and tapers over the next one to two days.
Primary dysmenorrhea accounts for a majority of the cases in which no pathologic lesions can be found in pelvic or laparoscopic examination. Although the exact etiology is unspecified, recent advances in biochemistry of prostaglandins to study chemicals and their role in pathophysiology have now established a rational basis for some cases of dysmenorrhea. The release of prostaglandins is significantly increased during menstruation in these women, and the release can be suppressed to normal levels when non-steroidal anti-flammatory drugs (NSAIDs) are given, since NSAIDs are capable of inhibiting cyclo-oxygenase and synthesis of prostaglandins.
In addition to NSAIDs, oral contraceptives, antispasmodics, and analgesics are commonly used by physicians. Androgen therapy is sometimes used, and a minor surgery called dilation and curettage (DandC) is also adopted in certain cases.
Traditional treatments are associated with a variety of side effects, including ineffectiveness and drug tolerance, and have limited effects. That explains why primary dysmenorrhea is still a problem. The present invention was developed using the most common herbal formulations in Traditional Chinese Medicine (TCM). This invention uses a different approaching characterized by steady effectiveness and relatively low toxicity.
The Cinnamomi and Poria composition is synthesized to protect women from the pain caused by most common pelvic diseases or disorders. In addition to treating primary and secondary dysmenorrhea and dysfunctional uterine bleeding caused by irregular shedding of uterine endometrium, the composition is also effective in treating chronic pelvic inflammations, inflammatory lower abdominal masses and small intramural hysteromyoma.
Like most TCM products, the Cinnamomi and Poria composition is prepared from multiple medicinal herbal materialsxe2x80x94five cultivated natural plants called Ramulus Cinnamomi, Poria, Cortex Moutan, Radix Paeoniae Alba and Semen Persicae. Different in weights and portions of the medicinal herbs for the start-up materials and in the producing courses, Cinnamomi and Poria composition shares the same formula of five herbs with a previous medicinal preparationxe2x80x94Bolus of Cinnamomi and Poria (BCP).
BCP, which has long been approved as an effective cure, was a sample of success in medicinal practice in ancient China. The formula of five was sourced from Jinkui Summary, a guide compiled by famous TCM practitioner Zhongjing Zhang, some 1,000 years ago. It was also collected in many medicine directory resources, such as the xe2x80x9cTraditional Chinese Medicine Dictionary.xe2x80x9d
With different courses of preparation, the five-plant formula was always administered in combination with other medicinal herbs. It claims to treat a variety of diseases and disorders, including many indications in the present invention.
As a comparison, while BCP was prepared by the extraction of herbs"" water solutionxe2x80x94a more traditional way in TCM practice, the present invention is produced by updated technologies which could better preserve its effective ingredients. Cinnamomi and Poria composition was developed in 1989, and have obtained the Certificate of New Medicine Product Permit by authorities in China.
In regards to the medicinal herb materials and their ingredients involving in present invention, a variety of United States Patents and literatures that taught methods in composing curative compositions from herbs like Cinnamomi, Poria etc. A variety of reports from China, country of the inventor, are also cited which were mostly in connection with animal or clinical researches for BCP and certain embodiment of Cinnamomi and Poria composition.
In U.S. Pat. No. 6,093,403, the formula consist an extract of Poria composition up 5 to 20% in weight are been used as a cure or prevention of disorders in sugar balance, diabetes, and such blood circulation diseases such as Angina Pectoris. Poria cocos wolf is being use for treating diseases occurred in area of cardio, cerebro-vascular, and for that of Alzheimer""s and depression. In U.S. Pat. No. 5,589,182 contain Poria cocos wolf up to 20% of its weight make up.
During the menopause stage for many women, many of them might experience a period, which is called xe2x80x9cHot Flashesxe2x80x9d. In U.S. Pat. No. 58740874, which is a herbal formula for treating women, who are in the stage of Hot Flashes. This herbal formula contains both Peony Root and Poria Cocos, making up to 13.3% of the weight of the formula.
U.S. Pat. No. 5,942,233, discloses a composition that consists of semen Persicae (Peach Kernel) up 30% of its weight. This formula is known for usages on blood stimulation and the flow of vital energy.
A pharmaceutical liquid composition which contains Cinnamomi Cortex is disclosed in U.S. Pat. No. 5,225,203 which amount 66 parts and 56 parts in Paeoniae Radix of its weight. This pharmaceutical liquid was used in hospital everywhere for treating patients that are suffering from stroke, arteriosclerosis, hypertension, tachycardia, dyspnea, anxiety, cardiostenosis, acute and chronic convulsion, automatic nervous system disease, and coma.
Another pharmaceutical liquid composition containing Paeoniae Radix and Cinnamomi Cortex are allegedly being used in U.S. Pat. No. 5,133,964, which presents an invention that relates to the preparation of oral and parental natural substance liquids of improve on physical stability. In this formula, it contains about 66 mg of Cinnamomi Cortex and 56 mg of Paeoniae Radix. The formula is also being used for the same treatments as described in U.S. Pat. No. 5,225,203.
U.S. Pat. No. 4,613,591 describes an adminiculum for antitumor agents. The composition consists both of Cinnamomi Cortex and Paeoniae Radix from 2.0 to 4.0 parts of the formula. The composition is used as a control substance for side effects and adminiculum for mitomycin C and doxorubicin.
Xie, J Z et al. published an article in 1986 on BCP""s influences on blood flow of rabbits. Xie says that BCP had long been claimed for its effect against hypostasis. In their test on rabbits both with oral and intravenous administration, Xie observed that the whole blood reduced specific viscosity and plasma specific viscosity were lowered, RBC electrophoresis time shortened and fibrinogen reduced.
Tu, Z K S et al. in 1988 reported their research results or oral administration of BCP in 10 health human bodies on their blood flow, blood platelet functions etc. The results showed that the whole blood viscosity was significantly lowered after two weeks of administration, the blood platelet coagulation induced by collagen and ADP and synthesis of thromboxane B2 in blood platelets was also inhibited. But, the diagrams of thrombus elasticity showed no changes.
Xie, J Z et al. reported BCP""s effect on central nerve system in 1987. Xie reported that oral and injection of BCP in mice both lead to a significant analgesia and sedation effect to the animals. Xie further pointed out that the half lethal dose was 80.0xc2x110.9 g/kg if given through subcutaneous injection, and over 250 g/kg if given orally.
He, H Q et al. published an article in 1994 on clinical study of Cinnamomi and Poria composition in 100 cases of gynecopathies: dysfunctional uterine bleeding caused by irregular shedding of uterine endometrim, chronic pelvic inflammations, dysmenorrhea and small intramural hysteromyoma. In comparison with 50 cases of patients that were treated with BCP, observations over multiple complaining symptoms and physical signs had showed no significant difference between the two groups.
Shi, D M et al. reported in 2000 after observing of therapeutic effects of Cinnamomi and Poria composition in 60 patients with hysteromyoma. Patients accepted physical examination on gynecology, ultrasonic examination and hematochrome test. The effectiveness of treatment was defined as significant improvement: tumor reduced 3-5 cm and enlarged menstrual flow reduced 50% or over; improvement: tumor reduced 2-3 cm and menstrual flow reduced 25% or over and ineffective: under improvement. The results showed in Shi""s report that an effective rate of 91.7% was acquired, and among which, 10% of the cases was of significant improvement.
In one embodiment of the invention, Capsule of Cinnamomi and Poria (CCP) was made. And pre-clinical studies on CCP""s pharmacological effects have showed that it has the effects of uterine smooth muscle relaxation, antispasmodic, pain-releasing and anti-inflammation, best explanation for its indication of dysmenorrhea and chronic pelvic inflammations.
Cinnamomi and Poria composition with different concentrations may cause an inhibitory effect against the contraction of extra-corporeal uterine of rats. It counteracts the acceleration and enhancement of contractions of the extra-corporeal uterine that was induced by oxytocin. Cinnamomi and Poria composition solution of different concentrations might result in the decrease of blood platelet agglutination rate in rats. The effectiveness had a positive relation with different concentrations. Cinnamomi and Poria composition could also induce a downfall of blood viscosity in rats administered with it for a few days.
Reaction to pains caused by chemical or heat, mice will twist their bodies or swing their tails. By recording the times of body twisting or tail swinging, an objective index of their feeling of pains could be evaluated. CCP, if given to the animals a few days before the tests, will, within certain scope, relieve them from the body movement.
For the effect of anti-inflammation, it could be observed that with administration of CCP, the weights of mice""s swelling ears were reduced obviously. The weight of mice""s swelling ear reflects the severity of inflammation in the ear that was smeared with croton oil at its surface a period of time before.
A general study of pharmacology on rats"" cardiovascular, respiration and nerve system showed that CCP had no noticeable reverse effect physiologically on the above systems. The acute toxicity test was conducted on 20 mice with 246 g/kg in dosage (a thousand times of human""s clinical dosage), administered by gastric injection. No death or any other abnormal activities were found. The 90 days long-term toxicity study was also negative in general health indexes, general blood perimeters, functions and pathological studies of different organs.
The controlled clinical studies of multi diseases and comprehensive evaluations were conducted among women of China. 150 people were involved in the first stage trial (Phase II). No deaths or serious adverse events had been reported. The clinical studies showed positive results in a comprehensive evaluated analysis: the evaluation to a multiple indications: dysmenorrhea, chronic pelvic inflammations and many others.
This invention provides a method for identifying a composition of Cinnamomi and Poria comprising the steps of: a) dissolving the composition of Cinnamomi and Poria with an appropriate aqueous solution mixed with an appropriate organic solvent; and b) performing gas chromatographic analysis using a HP-5 5% phenyl methyl siloxane capillary column.
This invention also provides a method for identifying a composition of Cinnamomi and Poria comprising the steps of: a) dissolving the composition of Cinnamomi and Poria with an aqueous solution; and b) separating the dissolved mater with an C 18 column under high pressure liquid chromatography.
This invention furthermore provides a method for identifying a composition of Cinnamomi and Poria comprising: extracting the composition of Cinnamomi and Poria by an appropriate organic solvent; using appropriate standard for liposoluble matter in the composition of Cinnamomi and Poria, as internal control; and performing high pressure liquid chromatography using a C18 column.
Furthermore, this invention provides a composition comprising: a) 1.3-1.9% paeoniflorin and b) 0.7-1.1% Paeonol.
This invention provides a method for obtaining a composition of Cinnamomi and Poria comprising steps of: a) obtaining, pruning, washing and cutting the plant parts: stem of Cinnamomum cassia Presl (Fam. Lauraceae), fungus of Poria cocos (Schw.) Wolf (Fam. Polyporaceae), Root of Paeonia suffruticosa Andr. (Fam. Ranunculaceae). and fruit of Prunus persica (L.) Batsch or Prunus davidiana (Carr.) Franch. (Fam. Rosaceae); b) drying the said plants to form 5 medicinal materials: Ramulus Cinnamomi, Poria Cortex, Moutan Radicis, Radix Paeonize Alba and Semen Persicae Semen Prunus; c) Smashing Ramulus Cinnamomi, Semen Persicae and Moutan Radicis into coarse powders and chopping Radix Paeonize Alba into slice; d) Sterilizing the Poria Cortex before granulating 50% of its formula weight into fine powder and filtering the powder; e) putting full amount of powder of Cortex Moutan through a process of hot reflux in water and collecting its distillate; (residue and fluid reserved); f) filtering and vacuum drying said distillate to obtain crude Paeonol; g) dissolving the curde paeonol into 95% alcohol; Slowly adding the solution into saturated water solution of xcex2-cyclodextrin while agitating it at thermostatic 80xc2x0 C. to form a mixture A; h) exhausted filtering mixture A; washing the residue with anhydrous alcohol and letting it dried, a clathrate A is obtained; i) distilling full amount of Ramulus Cinnamomi in water for four hours and collecting its volatile matter; (residue and fluid reserved) j) dissolving the volatile matter into 95% alcohol; slowly adding the solution into saturated water solution of xcex2-cyclodextrin while agitating it at thermostatic 45xc2x0 C. to form a mixture B; k) exhausted filtering mixture B; washing the residue with anhydrous alcohol and letting it dried, a clathrate B is obtained; 1) mixing residues from step (f) and (j) with full amount of Radix Paeonize Alba, Semen Persicae, 50% of Poria Cortex and 90% alcohol; extracting the mixture, filtering the extract and recovering alcohol from the filtered extract; (residue reserved) m) adding water in residue from step (m), distilling it and filtering the water extract; n) mixing water extract from step (n), alcohol extract from step (m), fluid from step (f) and step (j); enriching the mixture to form a creamed extractive; o) mixing the creamed extractive with Poria Cortex powder from step (e); grinding the mixture into fine powder after vacuum drying it to form a granule; p) mixing the fine powder with some 60% alcohol and starch gum; Granulating the powder to 30 meshes; q) mixing certain amount of silicon dioxide with clathrate A from step (i) and clathrate B from step (l); and r) mixing the mixture from step (r) with the granule from step (p) to obtain a final granulexe2x80x94the composition of Cinnamomi and Poria.
Furthermore, this invention provides a pharmaceutical composition for treating gynecological blood stasis, cardio-cerebral vascular diseases, respiratory system and urinary system diseases comprising the following materials in weight proportion: Ramulus Cinnamomi, 1-2 portion; Poria Cortex, 1-2 portion; Moutan Radicis, 1-2 portion; Radix Paeonize Alba, 1-2 portion; and Semen Persicae, 1-2 portion.
Finally, this invention also provides a method for obtaining a composition comprising: distilling a required amount of Cortex Moutan with water through a process of hot reflux and collecting its distillate, filtering and drying said distillate after its cooling down to obtain crude Paeonol; mixing the residues with required amount of Ramulus Cinnamomi, Radix Paeonize Alba, Semen Persicae and 50% of Poria Cortex, adding alcohol to the mixture and extract, extracting the mixture, filtering the extract to obtain an alcohol extract; adding water to residue from the alcohol extraction, extracting and filtering it to obtain a water extract; Mixing the alcohol extract, water extract and solution from distilling of Cortex Moutan, enriching the mixture to a creamed extract; and granulating the rest 50% of Poria Cortex into fine powder, mixing the fine powder with the creamed extract, granulating the mixture after vacuum drying, mixing the granule with crude Paeonol; and filling the mixture in to capsules to form the product.